Inactivation of human sodium channels and the effect of tocainide

Abstract

The inactivation of the sodium channels in human medulloblastoma cells was investigated with the whole-cell recording technique. The potential dependence of inactivation ("inactivation curve") was determined by imposing a series of prepulses of varying amplitude on the membrane potential and measuring the maximum sodium current flowing after each prepulse at the test potential of -20 mV. The time dependence of inactivation was investigated by determining inactivation curves with prepulses of variable duration. A prolongation of the prepulse increased the degree of inactivation, even when the prepulse duration was much greater than the time constant for fast inactivation. This is explained by the existence of two additional states of "intermediate" inactivation of the sodium channel, the transition to which is slower than that to the state of fast inactivation and faster than that to the state of slow inactivation. The antiarrhythmic drug tocainide had no effect on fast inactivation, but a strong effect on intermediate inactivation. This explains the use dependence of this drug. The reaction model given by Chiu (1977) for the transitions from the open into the closed state of inactivation and vice versa is extended.

Characteristics of two slow inactivation mechanisms and their influence on the sodium channel activity of frog ventricular myocytes

“…These authors reported a leftwards shift of the steady-state inactivation curve with increasing duration of the conditioning pulses. Similar shifts in the combined steady-state inactivation processes have been reported in sheep cardiac Purkinje fibres [21], rat brain Na + channel IIA expressed in Xenopus oocytes [15], human neuroblastoma cells [11] and rat dorsal root ganglion [18].…”

A sequence motif responsible for ER export and surface expression of Kir2.0 inward rectifier K+ channels

“…Other Kir channel subunits such as Kir4.1, which in native tissue do efficiently localize to the plasma membrane [11,13,21], might require interacting cofactors carrying ER export sequences themselves or prolonging channel half‐life within the surface membrane. First candidates would be other heteromerizing Kir channel subunits [22,23] and PDZ domain scaffold proteins, known to be coexpressed with Kir4.1 in native tissue [18,21,24].…”

Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use‐dependent block of skeletal muscle Na+ channels enhancing the antimyotonic activity in vivo

“…Tocainide has been previously shown to shift the steady‐state inactivation curves (h∞ curves) toward more negative potentials in a manner dependent on the duration of the depolarizing prepulse, implying a voltage‐ and time‐dependent reduction of the number of channels available for opening, principally due to a preferential binding of this drug to sodium channels in an inactivated state that, in turn, explains the use‐dependence of tocainide (Fakler et al ., 1990; Tricarico et al ., 1991; de luca et al ., 1991, 1997a).…”